tbuckley/cabot-search huggingface dataset:
Highlights of This Issue
Journal: Clinical Cancer Research (2015)

Molecular imaging with targeted probes could improve diagnosis, staging, and monitoring of pancreatic ductal adenocarcinoma. Kimbrough and colleagues utilized a novel imaging technology, multispectral optoacoustic tomography, which detects acoustic signals generated by electromagnetic stimulation of probes. Their probe, V7-750, was designed to target acidic extracellular pH and thus improve tumor detection. The V7-750 probe specifically accumulated within pancreatic tumors in mice as compared with pH-insensitive, K7-750 probe, as detected using MSOT, thus demonstrating promise as the basis of a clinically relevant tool in detection of cancer and possible monitoring in patients.Development of chemoresistance is an underlying cause for the majority of cancer therapy failures. The Notch signaling pathway has potential to promote chemoresistance through its ability to promote survival signals and cancer-like stem cells. To determine if inhibition of Notch signaling diminishes chemoresistance, Cui and colleagues evaluated the adjuvant activity of a γ-secretase inhibitor (GSI) in models of prostate cancer. The GSI enhanced docetaxel-mediated tumor response through inhibiting both cell survival signaling and generation of cancer-like stem cells. These results suggest that Notch pathway inhibition has potential to serve as an adjuvant to extend the effectiveness of chemotherapeutics.Castration-resistant prostate cancer (CRPC) is a major challenge in prostate cancer treatment, but no effective treatment targeting CRPC is currently available. Wang and colleagues demonstrated the existence and the functional roles of autocrine cholinergic system in prostate cancer. Activation of cholinergic muscarinic receptor 3 (CHRM3) promoted prostate cancer growth and castration resistance. Blockade of CHRM3 by shRNA or selective antagonist darifenacin effectively inhibited prostate cancer growth and castration resistance both in vitro and in vivo. These findings suggest that blockade of CHRM3 may represent a potential adjuvant therapy in prostate cancer treatment.EGFR-TKI resistance represents a major challenge for NSCLC patients' treatment. Because the Hedgehog pathway is an important mediator of epithelial-to-mesenchymal transition, the authors studied Hedgehog signaling activation in preclinical models of EGFR-TKI resistance. SMO gene amplification, concomitantly with MET activation, was identified for the first time as a novel mechanism of EGFR-TKIs' acquired resistance in an EGFR-mutated NSCLC model, supporting the rationale for a combined therapy. Also, in EGFR-wild-type NSCLC models, concomitant inhibition of Hh and EGFR reverts EGFR-TKI resistance. In light of these results, screening of SMO alterations is strongly recommended in NSCLC patients at first progression to EGFR-TKI therapy.
Highlights of This Issue
Journal: Clinical Cancer Research (2015)

Although preclinical mice models often fail to accurately predict the antitumor activity and toxicity of new therapies, comparative oncology has revealed that spontaneous lymphomas in dogs share many similarities with their human counterparts. Tierny and colleagues designed a dose escalation and biomarkers trial in dogs with naturally occurring lymphoma and demonstrated that F14512, a new vectorized anticancer drug currently in Phase I/II clinical trial in patients, can be safely administered to dogs resulting in strong therapeutic efficacy. This study has translational relevance for both the treatment of lymphomas in humans and the ongoing clinical development of F14512.BRAF inhibitors (BRAFi) can promote the growth of cutaneous squamous cell carcinomas with MAPK pathway mutations. Amaravadi and colleagues report that in a series of BRAF mutant melanoma patients treated for &gt;2 years with a BRAFi, multiple gastrointestinal polyps, including tubular colonic adenomas and hyperplastic gastric polyps, were observed. Genotyping identified no MAPK pathway mutations, but tubular adenomas had APC mutations. Treatment of APC Min +/− mice with BRAFi significantly increased polyp number compared to control, suggesting BRAFi can promote the growth of gastrointestinal polyps. Adenocarcinoma was not identified even in rechallenged patients, so the potential for accelerated polyposis should not preclude using BRAFi in BRAF mutant melanoma.Invasive cervical cancer patients in Guatemala and Venezuela have an average age at diagnosis of 50 years and 5.6 children each. Although HPV16 and HPV18 are the predominant types in tumors, there is considerable viral diversity in Guatemala. Sequencing of tumors from these countries and Mexico reveals frequent mutations in the helical domain of the PIK3CA gene; however, the E542K and E545K mutations do not activate AKT. Therefore therapies targeting PIK3CA directly or the as-yet-undescribed downstream targets are required.Distant metastases are frequently drug resistant and are heavily implicated in breast cancer mortality. McBryan and colleagues sought to characterise the global expression changes occurring with metastatic disease progression in the endocrine-resistant setting. Using RNAsequencing technology, the transcriptomes of sequential primary, nodal and liver metastatic tumors were profiled from tamoxifen-treated patients. Patient heterogeneity was evident as was a common need for tumor cells to adapt their cell-cell communications to facilitate successful colonisation of distant host organs. These findings emphasise the need for re-evaluation of tumor biology and ongoing personalized medicine throughout disease management.
Highlights of This Issue
Journal: Clinical Cancer Research (2015)

Immunotherapy with ipilimumab improves the survival of only around 20% of patients with metastatic melanoma. To explore reliable markers for the prediction of clinical outcome, Gebhardt and colleagues analyzed myeloid cells and related inflammatory factors in the peripheral blood of treated patients. Response to the therapy was associated with an early increase in eosinophil count, whereas nonresponders showed elevated amounts and function of circulating monocytic myeloid-derived suppressor cells as well as increased serum levels of S100A8/A9 and HMGB1. These novel complex predictive markers could help to identify metastatic melanoma patients who benefit from the ipilimumab therapy.The identification of biomarkers that early predicts the chemosensitivity of triple-negative breast cancers (TNBC) to standard neoadjuvant chemotherapy (NAC) is an important issue. Indeed, poorly responding women may be good candidates for emerging targeted therapy. Humbert and colleagues studied the predictive value of 18FDG-PET compared with clinicobiologic markers of TNBC. The authors demonstrated that combining positive EGFR status and a low 18FDG-PET tumor response after the first cycle of NAC can predict residual invasive carcinoma at the end of treatment. Multicenter trials using PET-guided treatment strategies are now necessary to evaluate the benefit of early therapeutic changes in poorly responding women.Clinical studies have demonstrated that tumor relapse after radiotherapy occurs preferentially in tumor areas with high 18F-fluorodeoxyglucose (FDG) uptake. To test the therapeutic gain from radiation dose escalation to the potentially radioresistant tumor subvolumes with high FDG, Trani and colleagues employed dose painting approaches in rat rhabdomyosarcoma: targeted dose escalation and dose redistribution. Although dose escalation to high FDG uptake was not superior to the same dose increase in low FDG uptake subvolumes, dose redistribution was even detrimental, consistent with the hypothesis that tumor response depends on the minimum intratumoral dose. These findings provide important information for the design of clinical trials.In HER2/ERBB2-amplified gastrointestinal tumors, concomitant HER2 targeting by trastuzumab antibody and the reversible inhibitor lapatinib is more effective than either agent alone. The mechanisms of this cooperation are unknown. Leto and colleagues found that trastuzumab and lapatinib complement each other to induce sustained neutralization of HER2 and its signaling partners HER3 and EGFR. This durable inhibition, which accounts for massive tumor shrinkage, is recapitulated by monotherapy with the HER2 irreversible inhibitor afatinib. These results provide functional evidence for the collaborative activity of trastuzumab and lapatinib and propose afatinib treatment as a means to diversify therapeutic opportunities in HER2-amplified gastrointestinal carcinomas.
Highlights of This Issue
Journal: Clinical Cancer Research (2016)

To determine whether a blood-based approach was suitable to select patients for BRAF-targeted therapies, Santiago-Walker and colleagues evaluated patients with BRAF mutation-positive tumors enrolled across four BRAF and MEK inhibitor trials for the presence of circulating BRAF mutation-positive DNA (BRAF-mut cfDNA). BRAF-mut cfDNA was detected in &gt;75% of patients. Lack of detectable BRAF-mut cfDNA correlated with longer progression-free survival, overall survival, and higher response rates, and may be an independent prognostic factor for disease outcome. The results show the feasibility of circulating BRAF-mut DNA detection and show that the absence of circulating BRAF mutation-positive DNA is clinically significant for metastatic melanoma patients.Epithelial-to-mesenchymal transition (EMT) contributes to drug resistance in multiple tumor types. To determine molecular alterations and drug targets associated with EMT—regardless of tissue of origin—a pan-cancer EMT gene signature was developed using patient tumors from 11 distinct cancer types. Cancers that had undergone EMT demonstrated common molecular alterations in mRNA, microRNA, and protein profiles, including higher expression of druggable immune checkpoints. These findings have important clinical implications and highlight the possibility of utilizing tumor EMT status to select patients who may benefit from immune checkpoint blockade.Tumor-infiltrating lymphocytes (TIL) confer prognostic benefit to patients with high-grade serous ovarian cancer (HGSC); however, the relationship to current standard-of-care remains underexplored. To address this, Wouters and colleagues determined prognostic benefit of TIL in two highly homogenous cohorts of HGSC patients. CD8+ TIL were of benefit only when tumors could be completely removed by cytoreductive surgery. By contrast, the less-differentiated CD27+ TIL subset also conferred a better prognosis in incompletely-cytoreduced patients. These findings have direct implications for assessment and characterization of TIL infiltrate as a biomarker for disease, relevant for prognosis of individual patients and patient selection in immunotherapeutic trials.The study identified the MYBL1, a homologue of the MYB gene, as a target of variable intra- and inter-chromosome 8q rearrangements in ACC. Alterations included frequent fusions of the gene with the NFIB and YTHDF3 genes only in tumors lacking t(6;9) and MYB-NFIB fusion transcript. The mutually exclusive nature of MYB/MYBL1 alterations and expression indicate a reciprocal interaction by two members of the same gene family in the development of ACC. These findings are critical to understanding the biology and identifying therapy targets for patients with this orphan and deadly cancer.
Highlights of This Issue
Journal: Clinical Cancer Research (2016)

The authors evaluated the safety and tolerability of the antisemaphorin 4D antibody VX15/2503 in a first-in-human study. Treatment-related adverse events were primarily Grade 1 or 2; one patient (15 mg/kg) experienced a Grade 3 DLT. No MTD was determined. Complete cellular SEMA4D saturation was generally observed at serum antibody concentrations ≥0.3 μg/mL, resulting in decreased ligand expression. One patient (20 mg/kg) experienced a PR and 27 patients exhibited SD for ≥8 weeks; subjects with elevated B/T lymphocytes exhibited longer progression-free survival. Preclinical studies suggest that combining VX15/2503 with immune modulating agents may improve the clinical activity of checkpoint blockade inhibitors.Triple-negative breast cancers (TNBCs) were reported in population-based studies to be more aggressive with a higher 5-year mortality than non-TNBCs. Podo and colleagues compared phenotype features and survival rates of invasive TNBCs versus non-TNBCs detected during the Italian 18-center HIBCRIT-1 study on screening of asymptomatic women at high genetic-familial risk for breast cancer. Combining an annual screening including magnetic resonance imaging with adequate treatment options, the 5-year overall survival (86% versus 93%) and disease-free survival (77% versus 76%, respectively) were not significantly different, thus showing the possibility of reducing the gap in outcome between TNBCs and non-TNBCs in high-risk women.There is a vital need for effective targeted therapeutics for triple-negative breast cancer (TNBC) patients, yet treatment strategies are challenged by the substantial intertumoral heterogeneity within TNBC. The receptor tyrosine kinase MET is highly expressed in several TNBC subtypes and is a promising therapeutic target. Using the tyrosine kinase inhibitor cabozantinib (XL184), Sameni and colleagues demonstrated that cabozantinib significantly inhibited TNBC growth and invasion in 3D in vitro models and in vivo, yet was ineffective against METneg TNBC cells. These results demonstrate that cabozantinib inhibition may be an effective treatment strategy for TNBC patients.RhoA, the founding member of the Rho GTPase family, is mutated in a large proportion of human diffuse gastric cancers (DGC). To explore the clinical significance, Yoon and colleagues examined RhoA activity in DGC cells, xenografts, and human tumors. RhoA was found to maintain DGC stem-like cells, promote epithelial to mesenchymal transition and chemotherapy resistance, and correlate with poor overall survival in DGC patients. Chemotherapy resistance could be overcome with RhoA inhibition, and thus RhoA is a promising new target in DGC.
Highlights of This Issue
Journal: Clinical Cancer Research (2016)

Legat and colleagues report a clinical trial in 16 advanced-stage melanoma patients vaccinated with five tumor peptides, Montanide and IMP321/LAG-3Ig, a non-TLR agonist with interesting adjuvant properties including dendritic cell activation. The treatment was well tolerated. Combinatorial immune monitoring revealed multiple tumor antigen-specific CD8 and CD4 T-cell responses in most patients, supporting the further use of these vaccine components for the development of combination immunotherapies.Zabor and colleagues analyzed individual patient tumor data from a phase III clinical trial of vemurafenib versus dacarbazine in melanoma patients to identify criteria for tumor measures that correlated with OS. Correlation between OS and early response was weak no matter how the response was defined; however, a strong correlation was seen between OS and progression when defined as ≥50% increase in sum of tumor diameters or appearance of new tumors. These data suggest that tumor progression is a better surrogate endpoint for OS than tumor response, such as RECIST.Zhuang and colleagues studied whether targeting IL-1a inhibits NF-κB activity and suppresses PDAC cell growth. Previously, studies show that KRASG12V induces expression of IL-1a in genetically engineered mouse models that express mutant KRAS and p53 and in cell lines expressing KRASG12V with p16 knockdown. The authors also observed a correlation between mutant KRAS and IL-1a expression in PDAC patient samples. The experimental evidence suggests a combination of gemcitabine and IL-1 receptor antagonist can reduce PDAC cell growth by inhibiting IL-1a-induced NF-κB activity, thus suggesting a new therapeutic approach for PDAC.Poulain and colleagues analyzed the genomic landscape of CXCR4 somatic mutation in Waldenström macroglobulinemia (WM) combining deep sequencing and SNP array. The study showed existence of intraclonal (variation in coexpression of MYD88 and CXCR4 mutations) and interclonal (mutually exclusive BCR and CXCR4 mutations in MYD88L265P WM) heterogeneity of the molecular spectrum of CXCR4 mutation. Furthermore, CXCR4 mutated WM displayed a specific clinicobiologic and genomic and transcriptomic signature. This dataset further suggests the genomic heterogeneity of WM beyond the current indolent versus symptomatic classification.
Highlights of This Issue
Journal: Clinical Cancer Research (2016)

Niemann and colleagues describe global changes in the CLL microenvironment during treatment with the BTK inhibitor ibrutinib. They report on changes in cytokines and chemoattractants, T-cell subsets, and activation and demonstrate disruption of tumor-macrophage interactions in the bone marrow microenvironment. This work highlights the potent effects ibrutinib exerts on both the CLL cell and the tumor-microenvironment abating the chronic inflammatory drive in this disease. Mapping of the “new” tumor-microenvironment in patients on ibrutinib may inform the design of future clinical trials.The FDA's Office of Hematology and Oncology Products provide their perspective on patient-reported outcome (PRO) assessment in cancer trials. The authors describe existing PRO strategies and discuss new instruments that are becoming available. They consider focusing key PRO analyses on separate measures of symptomatic adverse events, physical function, and disease-related symptoms that are important contributors to health-related quality of life. Increased rigor in PRO measurement and trial conduct are necessary, and collaboration is needed to review new and existing tools to develop a PRO strategy suitable for the needs of all those who rely on PRO to inform treatment and policy decisions.Krepler and colleagues analyzed patient-derived xenografts established from melanoma patients relapsed on BRAF inhibitor therapy for possible mechanisms of resistance on the genomic and protein signaling levels. By combining these two data sets, they found that, while most tumors had reactivated the BRAF pathway, a subset had also activated PI3K or MET signaling as alternative drivers. Subsequently, the PDX were expanded under chronic BRAF inhibitor drug pressure, and rational second line combination therapies targeting the escape mechanisms were shown to be effective in preclinical in vivo trials.XPO1 mediates the nuclear export of critical proteins required for rectal cancer proliferation and radiation resistance. Ferreiro-Neira and colleagues evaluated the radiosensitizing effects of XPO1 inhibitor (selinexor) in preclinical models of rectal cancer. Selinexor was tested in combination with radiation fractions similar to that given in clinical practice. Combined treatment promoted nuclear survivin accumulation and subsequent depletion, resulting in increased apoptosis and enhanced radiation antitumoral effects. These findings provide a novel therapeutic option for improving radiation sensitivity in the setting of rectal cancer.
Highlights of This Issue
Journal: Clinical Cancer Research (2016)

Curti and colleagues correlated the graft composition with the clinical outcome of 17 elderly patients with AML undergoing NK cell immunotherapy after induction/consolidation. AML patients received NK cells from haploidentical KIR-ligand mismatched donors after immunosuppression, followed by interleukin-2. The authors demonstrated that larger size of donor alloreactive NK cell repertoire correlates with better response to immunotherapy. Such finding represents a proof-of-concept of the antileukemic role of NK alloreactivity and has implications for the choice of the most suitable donor.Molecular predictors of response and mechanisms of resistance to azacytidine in Myelodysplastic syndrome (MDS) remain largely unidentified. Abnormal Stat3/5 signaling is implicated in clonal hematopoiesis. To explore the Stat3/5 signaling architecture in MDS, Miltiades and colleagues performed functional phenotyping in MDS patients undergoing azacytidine treatment. The Stat3/5 signaling biosignature identified patients in poor prognosis and marked a pathophysiologically and prognostically relevant, azacytidine resistant, CD34+ subset, whose kinetics paralleled the disease course and response to azacytidine. Their findings suggest that the aberrant Stat3/5 biosignature in MDS may represent a response predictor and also a therapeutic target to overcome azacytidine resistance.A mutation in NPM1 is one of the most common recurring genetic lesions in AML. To explore its role in rendering acute leukemia cells susceptible to ixazomib, a recently approved second-generation proteasome inhibitor for multiple myeloma, Garcia and colleagues evaluated the oxidative stress response in mediating cytotoxic activity. A direct association was observed between NPMc+ expression in AML, reduced antioxidant responses, and enhanced sensitivity to an oral proteasome inhibitor that induces oxidative stress. These data suggest that intracellular determinants of antioxidant responses may be good predictors of therapeutic response to ixazomib.The high frequency of the IGHV1-2*04 immunoglobulin gene in splenic marginal zone lymphoma (SMZL) strongly indicates antigen selection in disease development. IGHV1-2*04 expressing cases account for one-third of all SMZL and constitute a disease subgroup with a distinctive profile of genomic aberrations and an overall worse prognosis, indicating that immune signaling mediated by distinctive immunoglobulin receptors may impact on SMZL clonal behavior and eventual patient outcome. The present study advances the understanding of SMZL pathogenesis showing that ongoing antigen involvement is relevant throughout the natural history of SMZL, particularly IGHV1-2*04 cases, thus offering a strong rationale for signaling inhibition therapy.